Metabolism-excitation coupling in the heart is mediated by ATP-sensitive potassium (KATP) channels. This project seeks to understand the cellular and molecular basis for metabolic control of ATP-sensitive potassium channels by sulfonylurea receptors in the intact heart. Preliminary studies provide significant new discoveries regarding the molecular basis of KATP channel function. We have made use of these discoveries to develop novel transgenes that allow us to express overactive mutant KATP channels in cardiac sarcolemmal membranes. We have generated transgenic mice in which pancreatic and cardiac sarcolemmal KATP channel properties are significantly changed through expression of mutant Kir6.2 subunits. These studies demonstrate dramatic differences in the response of pancreatic and cardiac KATP channels to cellular metabolism. In order to explain these differences, and to further understand metabolism-excitation coupling in the intact heart, we now propose experiments to address the following question: How do SUR2A and cellular environment confer the cardiac KATP channel phenotype? Previous work has contributed substantially to current understanding of the role and molecular basis of KATP channels. The results of the proposed experiments will bring insight to the regulation of these channels in the heart in vivo. The work will provide information that will ultimately underlie the development of rational therapies for the treatment of cardiac ischemia and arrhythmias.